Inhibitor for retinochoroidal disorders

ABSTRACT

The present invention addresses the problem of providing an inhibitor for retinochoroidal disorders, in particular, an inhibitor for retinochoroidal scar formation and retinochoroidal atrophy in an epiretinal, intraretinal or subretinal tissue. This problem can be solved by preparing an inhibitor for retinochoroidal disorders which comprises, as an active ingredient, (E)-4-(2-{3-[(1H-pyrazol-1-yl)methyl]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl}vinyl)benzoic acid, an ester thereof or a salt of the same. The inhibitor for retinochoroidal disorders can inhibit collagen atrophy of retinal pigment epithelium cells, fibroblasts, glial cells and the like and thus inhibit retinochoroidal disorders.

The present invention relates to an inhibitor of retinochoroidaldisorder comprising(E)-4-(2-{3-[(1H-pyrazol-1-yl)methyl]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl}vinyl)benzoicacid, an ester thereof or a salt thereof as an effective ingredient.

BACKGROUND ART

In Japan where the society has an aging population, the ratio ofvitreoretinal diseases such as diabetic retinopathy, retinal detachment,and age-related macular degeneration is expected to continue to increaseas a cause of blindness. Prognosis of such diseases, which resulted inblindness in the past, is improving by the development of vitreoretinaloperation and introduction of biopharmaceuticals, such as anti-VERFintraocular injections. However, aside from initial symptoms, theprognosis of visual functions in severe cases, where symptoms were leftuntreated for a long period of time or are recurring, is still notfavorable. Even if retinopexy is attained by an operation or intraocularneovascularity can be devised to disappear with a pharmaceutical agent,photoreceptor functions would decrease if retinal cells have alreadysuffered an irreversible secondary damage. Eyes are organs, for whichhealing of injury would be completely meaningless if photoreceptorfunctions are lost. Thus, in order to maintain normal retinal functions,it is important how an ophthalmic inflammation and the followingsecondary reaction can be controlled with the least amount of damage.

Along with the calming or progression of an ophthalmic inflammation, aretinochoroidal fibrotic scar is often formed in epiretinal,intraretinal, or subretinal tissue and in some cases leads to a disorderin photoreceptor cell functions. Collagen, which is one of thecomponents of the stroma and retinal pigment epithelial cells,particularly type I collagen, is known as a representative cellcomponent constituting a retinochoroidal fibrotic scar. Retinochoroidaldysfunction occurs due to the formation and atrophy of a retinochoroidalfibrotic scar. In this regard, it is considered effective againstretinochoroidal disorders to inhibit atrophy of collagen, particularlytype I collagen, of retinal pigment epithelial cells or the like toprevent deformation or disintegration of a tissue structure.

To date, a medicament for the prevention and/or treatment of diabeticretinopathy or age-related macular degeneration having an agonist of aretinoic acid receptor (hereinafter, also referred to as “RAR”),all-trans retinoic acid or4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid, as an effective ingredient (for example, seePatent Literature 1). However, since such an effective ingredient doesnot have selectivity with respect to RAR subtypes RARα and RARβ, thecontribution of each RAR subtype to improvement in the retinal functionis unknown. Meanwhile, RAR is involved in various effects such asgrowth, morphogenesis, and differentiation in many cells such asinflammatory cells, immune cells, and structural cells. Further, it isverified that there is a difference in the distribution of RAR subtypesdepending on the tissue or organ of a mammal. Some of the effects of RARare undesirable, such as increase in triglyceride due to RARα. Thus, thespecificity or selectivity with respect to subtypes in compounds withRAR agonist activity is expected to lead to reduction in risk of sideeffects. For the above reasons, there is a demand for RAR agonists,which have a strong effect of inhibiting retinochoroidal disorders andare highly safe based on subtype selectivity.

(E)-4-(2-{3-[(1H-pyrazole-1-yl)methyl]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl}vinyl)benzoic acid is disclosed to be useful as a RARγ selective agonistagainst pulmonary emphysema, cancer, and dermatosis (for example, seePatent Literature 2) and against neurological pain (for example, seePatent Literature 3). However, there is no study that has examined thepharmacological effect of(E)-4-(2-{3-[(1H-pyrazole-1-yl)methyl]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl}vinyl)benzoicacid, an ester thereof, or a salt thereof on retinochoroidal disorders,particularly the formation and atrophy of a retinochoroidal scar, or adocument suggesting such an effect.

[PTL 1] Domestic Publication of PCT International Publication No.2007/037188

[PTL 2] International Publication No. WO 2002/028810 pamphlet

[PTL 3] International Publication No. WO 2008/057930 pamphlet

SUMMARY OF INVENTION

The objective of the present invention is to provide an inhibitor for aretinochoroidal disorder, particularly an inhibitor for the formationand atrophy of a retinochoroidal scar in epiretinal, intraretinal, orsubretinal tissue.

The search for a drug that is effective against ophthalmic diseases,particularly retinochoroidal disorders in vitreoretinal diseases, is anobjective that is important and of interest in the field ofophthalmology. After diligent research to find a drug that is effectivein inhibiting retinochoroidal disorders, particularly the formation andatrophy of a retinochoroidal scar, the inventors discovered that theRARγ selective agonist(E)-4-(2-{3-[(1H-pyrazole-1-yl)methyl]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl}vinyl)benzoicacid exerts an excellent effect of amelioration in inhibiting theformation and atrophy of a retinochoroidal scar by pharmacological testsusing murine retinal pigment epithelial cells, wherein theabove-described benzoic acid exhibited an effect of inhibiting collagenatrophy and an effect of inhibiting the formation and atrophy ofsubretinal scars in mice to complete the present invention.

Specifically, the present invention is directed to [1] an inhibitor fora retinochoroidal disorder comprising(E)-4-(2-{3-[(1H-pyrazole-1-yl)methyl]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl}vinyl)benzoicacid, an ester thereof, or a salt thereof as an effective ingredient,[2] the inhibitor for a retinochoroidal disorder of the above-described[1], wherein the(E)-4-(2-{3-[(1H-pyrazole-1-yl)methyl]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl}vinyl)benzoicacid, the ester thereof, or the salt thereof is(E)-4-(2-{3-[(1H-pyrazole-1-yl)methyl]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl}vinyl)benzoicacid or a salt thereof, [3] the inhibitor for a retinochoroidal disorderof the above-described [1] or [2], wherein the retinochoroidal disorderis formation or atrophy of a retinochoroidal scar in epiretinal,intraretinal, or subretinal tissue, [4] the inhibitor for aretinochoroidal disorder according to any one of the above-described[1]-[3], wherein a form of administration is instillative administrationor oral administration, and [5] the inhibitor for a retinochoroidaldisorder accordingly to any one of the above-described [1]-[4], whereina dosage form is an instillation, an ophthalmic ointment, an injection,a tablet, a granule, a fine granule, a powder or a capsule.

(E)-4-(2-{3-[(1H-pyrazole-1-yl)methyl]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl}vinyl)benzoic acid, an ester thereof, or a salt thereof, which is an effectiveingredient of the inhibitor for a retinochoroidal disorder of thepresent invention, is useful as an inhibitor for retinochoroidaldisorders, particularly as an inhibitor for the formation and atrophy ofa retinochoroidal scar, by inhibiting collagen atrophy of a retinalpigment epithelial cell, fibroblast, glial cell or the like.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a graph showing the relationship between the concentration (0)of(E)-4-(2-{3-[(1H-pyrazole-1-yl)methyl]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl}vinyl)benzoicacid (hereinafter, also referred to as “benzoic acid of the invention”)and collagen atrophy (diameter (mm) of collagen gel in the dish) whenusing murine retinal pigment epithelial cells, wherein

indicates the presence of a statistically significant difference(p<0.05).

FIG. 2 FIGS. 2A-2B are graphs showing the results of studying the effectof inhibiting subretinal scar formation when the benzoic acid of theinvention is injected in murine subretinal scar model production. FIG.2A shows the results of subretinal observation after 7 days from theinjection of 50 μg of the benzoic acid of the present invention andmacrophages. FIG. 2B shows the results of measuring a subretinal scarregion after 7 days from injection when injecting 1 μg, 5 μg, or 50 μgof the benzoic acid of the invention and macrophages, wherein

indicates the presence of a statistically significant difference(p<0.05).

DESCRIPTION OF EMBODIMENTS

The inhibitor for a retinochoroidal disorder of the present invention isnot particularly limited and may be any inhibitor having the benzoicacid of the invention represented by the following formula (I), an esterthereof, or a salt thereof as the effective ingredient. However, thebenzoic acid of the invention or a salt thereof is preferable as aneffective ingredient. Further, other embodiments of the presentinvention include: a method of treating a retinochoroidal disordercharacterized in administering the benzoic acid of the invention, anester thereof, or a salt thereof to a subject; the benzoic acid of theinvention, an ester thereof, or a salt thereof for use as an inhibitorfor a retinochoroidal disorder; and use of the benzoic acid of theinvention, an ester thereof, or a salt thereof in the preparation of aninhibitor for a retinochoroidal disorder.

In the present invention, a retinochoroidal disorder refers to acondition in which an injury occurs to a photoreceptor cell, ganglioncell, retinal pigment epithelial cell or tissue comprised of each of theabove-described cells in the retina or choroid, ultimately leading tocell death or tissue dysfunction to cause disturbance in visual functionsuch as vision or field of vision. A retinochoroidal disorder issuitably exemplified by formation and atrophy of a retinochoroidal scarand vitreoretinal diseases such as diabetic retinopathy, age-relatedmacular degeneration, retinal detachment, proliferativevitreoretinopathy, uveitis, ocular infection, retinopathy ofprematurity, neovascular maculopathy, and retinochoroiditis. Aretinochoroidal disorder is particularly suitably exemplified byformation and atrophy of a retinochoroidal scar.

In the present invention, a retinochoroidal scar is a fibrous connectivetissue occurring at an epiretinal, intraretinal, or subretinal injurysite with the soothing or progression of an ophthalmic inflammation,preferably a fibrous connective tissue occurring at a subretinal injurysite, and is mainly tissue comprised of a retinal pigment epithelialcell, fibroblast, glial cell, or the like with extracellular matrixincluding collagen. In addition, the above-described epiretinal refersto on a retinal surface, subretinal refers to between the retina andchoroid, inside the choroid, and under the choroid. Further, formationof a retinochoroidal scar refers to the formation of a fibrousconnective tissue at an epiretinal, intraretinal, or subretinal injurysite with the soothing or progression of an ophthalmic inflammation.Atrophy of a retinochoroidal scar refers to the atrophy by a formedretinochoroidal scar pulling tissue in the periphery thereof uponhealing. Such formation and atrophy of a retinochoroidal scar occurs inseries. It is possible to prevent peripheral tissue and macular area ofa retinochoroidal scar from deforming to cause a disorder in theretinochoroidal function by inhibiting the formation and atrophy of theretinochoroidal scar.

The benzoic acid of the invention, an ester thereof, or a salt thereof,which is an effective ingredient of the therapeutic agent for aretinochoroidal disorder of the present invention, can be manufacturedin accordance with the method described in Patent Literature 2 describedabove or purchased as a commercially-available product. Examples of suchcommercially-available products include product name: palovarotenemanufactured by Shanghai Haoyuan Chemexpress.

Esters in the benzoic acid of the invention, an ester thereof, or a saltthereof, which is an effective ingredient of the therapeutic agent for aretinochoroidal disorder of the present invention, are not particularlylimited and can be any ester converted to the benzoic acid of theinvention in a reaction by an enzyme or the like under physiologicalconditions in vivo. Examples of such esters include: esters generated byreaction with a primary alcohol, such as methanol, ethanol, propanol,hexanol, dodecanal or the like; esters generated by reaction with asecondary alcohol such as isopropanol, s-butanol, 1-ethylpropanol or thelike; esters generated by reaction with a tertiary alcohol such ast-butanol, 1-methyl-1-ethylpropanol or the like; and esters generated byreaction with an amino alcohol such as 2-aminoethanol or the like.

The above-described esters can be manufactured by a known method fromthe benzoic acid of the invention or an intermediate during synthesisthereof.

Salts in the benzoic acid of the invention, an ester thereof, or a saltthereof, which is an effective ingredient of the inhibitor for aretinochoroidal disorder of the present invention, are not particularlylimited and can be any pharmaceutically acceptable salts. Such saltsinclude (1) as an acid addition salt, inorganic acid salts such ashydrochloride, hydrobromic acid salt, hydro iodic acid salt, nitric acidsalt, sulfuric acid salt, phosphoric acid salt and the like; and organicacid salts such as acetic acid salt, trifluoroacetic acid salt, benzoicacid salt, oxalic acid salt, malonic acid salt, succinic acid salt,maleic acid salt, fumaric acid salt, tartaric acid salt, citric acidsalt, methanesulfonic acid salt, ethanesulfonic acid salt,trifluoromethanesulfonic acid salt, benzenesulfonic acid salt,p-toluenesulfonic acid salt, glutamic acid salt, aspartic acid salt andthe like and (2) as a basic salt, metal salts such as sodium salt,potassium salt, calcium salt, magnesium salt and the like; inorganicsalts such as ammonium salt and the like; and organic amine salts suchas triethylamine salt, guanidine salt and the like.

The inhibitor for a retinochoroidal disorder of the present inventioncan be administered orally or parenterally (intravenous administration,intramuscular administration, intraperitoneal administration,percutaneous administration, intratracheal administration,intracutaneous administration, or subcutaneous administration) in a formof an ointment (preferably ophthalmic ointment), injection, tablet,granule, fine granule, powder, capsule, inhalant, syrup, pill, liquidformulation, suspension, emulsion, percutaneous absorption agent,suppository, or lotion manufactured by mixing in a suitablepharmacologically acceptable additive. These formulations aremanufactured by a well-known method by using an additive such as anexcipient, lubricant, binding agent, disintegrator, emulsifier,stabilizer, flavoring agent or diluent.

Examples of excipients include organic excipients and inorganicexcipients. Examples of organic excipients include: sugar derivativessuch as lactose, sucrose, glucose, mannitol, sorbitol and the like;starch derivatives such as corn starch, potato starch, α-starch, dextrinand the like; cellulose derivatives such as crystalline cellulose andthe like; gum arabic; dextran; pullulan and the like. Examples ofinorganic excipients include: light anhydrous silicic acid; and sulfuricacid salts such as calcium sulfate and the like.

Examples of lubricants include: stearic acid; metal salts of stearicacid such as calcium stearate, magnesium stearate and the like; talc;colloidal silica; wax such as beeswax, spermaceti and the like; boricacid; adipic acid; sulfuric acid salts such as sodium sulfate and thelike; glycol; fumaric acid; sodium benzoate; D,L-Leucine, sodium laurylsulfate; silicic acids such as silica and silicic acid hydrate; and thestarch derivatives and the like for the above-described excipients.

Examples of binding agents include hydroxypropyl cellulose,hydroxypropyl methylcellulose, polyvinylpyrrolidone, macrogol and thecompounds described above shown for excipients.

Examples of disintegrators include: cellulose derivatives such ashydroxypropyl cellulose with a low degree of substitutions,carboxymethyl cellulose, calcium carboxymethyl cellulose, and internallycrosslinked calcium carboxymethyl cellulose and the like; crosslinkedpolyvinylpyrrolidone; and chemically modified starch or cellulosederivatives or the like such as carboxymethyl starch and sodiumcarboxymethyl starch and the like.

Examples of emulsifiers include: colloidal clay such as bentonite andveegum and the like; anionic surfactants such as sodium lauryl sulfateand the like; cationic surfactants such as benzalkonium chloride and thelike; and non-ionic surfactants and the like such as polyoxyethylenealkyl ether, polyoxyethylene sorbitan fatty acid ester, and sucrosefatty acid ester and the like.

Examples of stabilizers include: para-hydroxybenzoic acid esters such asmethylparaben, propylparaben and the like; alcohols such aschlorobutanol, benzyl alcohol, and phenylethyl alcohol and the like;benzalkonium chloride; phenols such as phenol and cresol and the like;thimerosal; acetic anhydride; and sorbic acid.

Examples of flavoring agents include: sweeteners such as sodiumsaccharin and aspartame and the like; acidulants such as citric acid,malic acid, and tartaric acid and the like; and flavors such as menthol,lemon extract and orange extract and the like.

Diluents are generally compounds used as a diluent. Examples thereofinclude lactose, mannitol, glucose, sucrose, calcium sulfate,hydroxypropyl cellulose, microcrystalline cellulose, water, ethanol,polyethylene glycol, propylene glycol, glycerol, starch,polyvinylpyrrolidone, mixtures thereof and the like.

For ointments (preferably ophthalmic ointments), a commonly-used basesuch as white petrolatum or liquid paraffin or the like can be used forpreparation.

The inhibitor for a retinochoroidal disorder of the present inventionincludes those in a form of instillation in addition to theabove-described dosage forms. The above-described instillation can beinstillatively administered. The agent can be formulated with awell-known method by suitably blending in an isotonizing agent, buffer,pH regulator, solubilizer, thickener, stabilizer, preservative(antiseptic) or the like as an additive. Further, it is also possible toobtain a stable instillation by adding a pH regulator, thickener,dispersant or the like to prepare suspension of a drug.

Examples of isotonizing agents include glycerin, propylene glycol,sodium chloride, potassium chloride, sorbitol, mannitol and the like.

Examples of buffers include phosphoric acid, phosphate, citric acid,acetic acid, ε-aminocaproic acid and the like.

Examples of pH regulators include hydrochloric acid, citric acid,phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide,boric acid, borax, disodium hydrogen phosphate, sodium dihydrogenphosphate, sodium carbonate, sodium bicarbonate and the like.

Examples of solubilizers include polysorbate 80, polyoxylethylenehydrogenated castor oil 60, macrogol 4000 and the like.

Examples of thickeners and dispersants include: cellulose polymers suchas hydroxypropyl methylcellulose, hydroxypropyl cellulose and the like;polyvinyl alcohols; polyvinylpyrrolidone and the like. Further, examplesof stabilizers include edetic acid, sodium edetate and the like.

Examples of preservatives (antiseptics) include commonly-used sorbicacid, potassium sorbate, benzalkonium chloride, benzethonium chloride,methyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanoland the like. It is also possible to use these preservatives incombination.

An instillation may have any pH within a range acceptable for anophthalmic formulation, but the pH is desirably set to 4.0-8.5.

The dosage of the inhibitor for a retinochoroidal disorder of thepresent invention can be appropriately changed in accordance with thedosage form, severity of symptoms of a patient to whom the agent is tobe administered, age, weight, judgment of a physician or the like. Fororal agents, it is generally possible to administer 0.01-5000 mg,preferably 0.1-2500 mg, and more preferably 0.5-1000 mg per day for anadult in one or several doses. For instillations, it is possible toadminister those with an effective ingredient concentration of0.000001-10% (W/V), preferably 0.00001-3% (W/V), and more preferably0.0001-1% (W/V), in one or several daily doses. For ophthalmicointments, it is possible to administer those with an effectiveingredient concentration of 0.00001-10% (W/V), preferably 0.0001-3%(W/V), and more preferably 0.001-1% (W/V), in one or several dailydoses.

Hereinafter, the present invention is illustrated in further detailwhile providing Examples (Test Examples and Drug Formulation Examples).However, the scope of the present invention is not limited thereto.

EXAMPLES Example 1

(Test on Inhibition of Three-Dimensional Collagen Gel Atrophy in MurineRetinal Pigment Epithelial Cell)

Murine retinal pigment epithelial cells were used to assess theinhibition effect of a tested compound on three-dimensional collagen gelatrophy in accordance with the method of Nishida et al (InvestigativeOphthalmology & Visual Science 42: 1247-1253 (2001)). A subretinalsheet-like pigment epithelial cell comprising a retinal pigmentepithelial cell from a mouse eyeball was collected and grown in primaryculture. The cultured cell was detached and collected from a cultureslide with 0.05% Trypsin-EDTA. After washing twice in a serum freemedium (MEM: product number 11095; Gibco), a serum-free medium was addedto make a cell suspension. Type I collagen (3 mg/ml: product number637-00653; Nitta Gelatin Inc.), 10×MEM, reconstitution buffer (productnumber 635-00791; Nitta Gelatin Inc.), cell suspension (1.1×10⁷ cells/mlin MEM), and water were mixed on ice at the volume ratio of7:1:1:0.2:1.8. A culture dish coated with 1% BSA was inoculated with themixture (0.5 ml), which was incubated for one hour at 37° C. to make acollagen gel. Then, 0.5 ml each of serum free media, to which 1 ng/ml ofTGF-β2 (R&D) and 0, 0.01, 0.1, or 10 of the benzoic acid of theinvention were added, was added onto collagen gels and incubated at 37°C. The diameter of gels was measured after 24 hours. As a control, 0.5ml of only a serum-free medium was added and similarly incubated. Theresults are shown in FIG. 1 .

(Results)

It can be seen from FIG. 1 that the benzoic acid of the invention caninhibit collagen atrophy due to TGF when using murine retinal pigmentepithelial cells. This demonstrates that the benzoic acid of theinvention contributes to collagen turn over and is effective ininhibiting retinochoroidal disorders and has an effect of inhibitingtissue remodeling that occurs after inflammation, hemorrhage, infection,surgery, or injury in an ophthalmic tissue, i.e., retinal tissuefibrillation, retinochoroidal scar formation, and atrophy.

Example 2

(Test on Inhibition of Murine Subretinal Scar Formation)

A murine subretinal scar model was produced to study whether the benzoicacid of the invention has an effect of inhibiting subretinal scarformation. A subretinal scar model in a mouse was produced by the methodshown below in accordance with the method of Young-joon et al(Investigative Ophthalmology & Visual Science, 52, 6089-6095(2001)).

(Production of Murine Subretinal Scar Model)

First, laser was irradiated (0.05 seconds, 200 mW, 532 nm) onto onelocation on the posterior pole of fundus of mouse C57BL/6 (purchasedfrom SLC) to destroy the Bruch's membrane, which enabled infiltration ofinflammatory cells from the choroid as well as creation of air bubblessubretinally.

A 33 G needle was then inserted from pars plana. 0.5 μl of 4×10⁷ mlthioglycollate elicited peritoneal macrophage and 1 μg, 5 μg, or 50 μgof the benzoic acid of the invention were subretinally injected. For thecontrol, the benzoic acid of the invention was not injected (0 μg).

The subretinal area was observed and subretinal scar region was measure7 days after injection of the macrophage and the benzoic acid of theinvention described above. The results are shown in FIG. 2 .

(Results)

As shown in FIG. 2A, formation of a scar was inhibited when 50 μg of thebenzoic acid of the invention was injected in comparison to the control.Further, as shown in FIG. 2B, the scar region (fibrillation region)narrows as the amount of injection of the benzoic acid of the inventionincreases. Thus, it was revealed that formation and atrophy ofsubretinal scars can be inhibited by the benzoic acid of the invention.

Example 3

[Drug Formulation Example] (Drug Formulation Example 1) Instillation In100 ml Benzoic acid of the invention 100 mg Sodium chloride 800 mgPolysorbate 80 appropriate amount Disodium hydrogen phosphateappropriate amount Sodium dihydrogen phosphate appropriate amountSterile purified water appropriate amount

The benzoic acid of the invention and the other components describedabove are added to sterile purified water. The solution is thoroughlymixed to prepare an instillation. It is possible to prepare aninstillation with a concentration of 0.05% (W/V), 0.3% (W/V), 0.5%(W/V), or 1% (W/V) by changing the amount of the benzoic acid of theinvention or the like that is added.

(Drug Formulation Example 2) Ophthalmic Ointment In 100 g Benzoic acidof the invention  0.3 g Liquid paraffin 10.0 g White petrolatumappropriate amount

The benzoic acid of the invention is added to homogeneously-melted whitepetrolatum and liquid paraffin. The mixture is thoroughly mixed and thengradually cooled to prepare an ophthalmic ointment. It is possible toprepare an ophthalmic ointment with a concentration of 0.05% (W/V), 0.1%(W/V), 0.5% (W/V), or 1% (W/V) by changing the amount of the benzoicacid of the invention or the like that is added.

(Drug Formulation Example 3) Tablet In 100 mg Benzoic acid of theinvention 1 mg Lactose 66.4 mg Corn starch 20 mg Calcium carboxymethylcellulose 6 mg Hydroxypropyl cellulose 6 mg Magnesium stearate 0.6 mg

The benzoic acid of the invention, corn starch and lactose are mixed ina mixer. Calcium carboxymethyl cellulose and hydroxypropyl cellulose areadded to the mixture for granulation. The particle size of the resultinggranules is adjusted after drying. Magnesium stearate is added to andmixed with the adjusted granules and the mixture is made into tabletswith a tableting machine. Further, it is possible to prepare tabletswith the content of 0.1 mg, 10 mg, or 50 mg in 100 mg by changing theamount of the benzoic acid of the invention or the like that is added.

INDUSTRIAL APPLICABILITY

(E)-4-(2-{3-[(1H-pyrazole-1-yl)methyl]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl}vinyl)benzoic acid, an ester thereof, or a salt thereof, which is an effectiveingredient of the inhibitor for a retinochoroidal disorder of thepresent invention, is useful as an inhibitor for retinochoroidaldisorders, particularly as an inhibitor for the formation and atrophy ofa retinochoroidal scar, by strongly inhibiting collagen contraction in aretinal pigment epithelial cell, fibroblast, glial cell or the like inthe retinochoroid.

The invention claimed is:
 1. A method of inhibiting or reducing scarformation in the retina and/or choroid of a subject in need thereof,comprising administering to said subject palovarotene((E)-4-(2-{3-[(1H-pyrazole-1-yl)methyl]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl}vinyl)benzoic acid), an ester thereof, or a salt thereof, in an amounteffective to inhibit or reduce scar formation.
 2. The method of claim 1,wherein said scar formation on the retina and/or choroid is caused byinflammation, hemorrhage, infection, surgery, or injury in an ophthalmictissue.
 3. The method of claim 2, wherein said scar formation on theretina and/or choroid is caused by surgery.
 4. The method of claim 1,wherein said administering comprises administering orally,intravenously, intramuscularly, intraperitoneally, percutaneously,intratracheally, intracutaneously, subcutaneously, or by instillation.5. The method of claim 1, wherein said palovarotene is in the in theform of an ointment, injection, tablet, granule, fine granule, powder,capsule, inhalant, syrup, pill, liquid formulation, suspension,emulsion, percutaneous absorption agent, suppository, lotion, orinstillation.
 6. The method of claim 5, wherein said ointment is anophthalmic ointment.
 7. The method of claim 6, wherein the concentrationof said palovarotene in the ophthalmic ointment administered to saidsubject is from 0.00001% to 10% (w/w), from 0.0001% to 3% (w/w), or from0.001% to 1% (w/w).
 8. The method of claim 6, wherein the concentrationof said palovarotene in the ophthalmic ointment is 0.05% (w/w), 0.1%(w/w), 0.5% (w/w), or 1% (w/w).
 9. The method of claim 6, wherein theophthalmic ointment comprises a solubilizer.
 10. The method of claim 9,wherein the solubilizer is selected from the group consisting ofpolysorbate 80, polyoxyethylene hydrogenated castor oil 60, and macrogol4000.
 11. The method of claim 10, wherein the solubilizer is polysorbate80.
 12. The method of claim 5, wherein said palovarotene is in the formof liquid formulation.
 13. The method of claim 12, wherein theconcentration of said palovarotene in the liquid formulation is from0.000001% to 10% (w/v), from 0.00001% to 3% (w/v), or from 0.0001% to 1%(w/v).
 14. The method of claim 12, wherein the concentration of saidpalovarotene in the liquid formulation is 0.05% (w/v), 0.3% (w/v), 0.5%(w/v), or 1% (w/v).
 15. The method of claim 12, wherein the liquidformulation comprises a solubilizer.
 16. The method of claim 15, whereinthe solubilizer is selected from the group consisting of polysorbate 80,polyoxyethylene hydrogenated castor oil 60, and macrogol
 4000. 17. Themethod of claim 16, wherein the solubilizer is polysorbate
 80. 18. Themethod of claim 1, wherein said palovarotene is administered to saidsubject in one or more daily doses.
 19. The method of claim 1, whereinthe subject has age-related macular degeneration.